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Two novel mutations linked to ALK inhibitor resistance in NSCLC

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October 7, 2014

Two novel ALK mutations, V1180L and I1171T, were associated with resistance to crizotinib and alectinib but were sensitive to other next-generation ALK tyrosine kinase inhibitors for non–small-cell lung cancer, according to study results.

Although crizotinib (Xalkori, Pfizer) is the standard therapy for ALK-rearranged non–small cell lung cancer (NSCLC), patients often develop resistance to this agent and the next-generation ALK tyrosine kinase inhibitor (TKI) alectinib (CH5424802/RO5424802; Chugai Pharmaceuticals, Roche), according to study background information.

For this reason, Ryohei Katayama, PhD, of the Cancer Chemotherapy Center at the Japanese Foundation for Cancer Research in Tokyo, and colleagues sought to evaluate mechanisms of resistance to next-generation ALK TKIs.

Katayama and colleagues developed a human NSCLC cell line and generated resistant H3122 cells by increasing their exposure to alectinib over 7 months. They then examined coding sequencing of H3122 parental cells and resistant H3122 CHR-A1 cells, and identified the novel V1180L gatekeeper mutation.

Researchers also examined a tumor specimen from a patient who developed resistance to and relapsed on crizotinib and alectinib. Through fluorescent in situ hybridization analysis, they identified the novel I1171T mutation.

An analysis of EML4-ALK–expressing Ba/F3 cells that harbored V1180L and I1171T mutations confirmed that the mutations conferred resistance to crizotinib and alectinib. However, V1180L was associated with stronger resistance.

Using the Ba/F3 cells, the next-generation ALK TKI ceritinib (Zykadia, Novartis) demonstrated activity against the mutations. Ceritinib treatment of the patient from whom the cells were derived conferred a partial response that lasted for longer than 7 months.

Katerina Politi, PhD

Katerina Politi

“Until now, it was unknown whether patients could continue to derive benefit from ALK inhibition after failure of a next-generation ALK inhibitor,” Katayama and colleagues wrote. “Our results suggest that patients may benefit from multiple, sequential ALK inhibitor therapies, depending on the underlying mechanism of resistance.”

The findings suggest the need for routine biopsies in the management of patients with ALK-rearranged NSCLC, Katerina Politi, PhD, and Scott Gettinger, MD, both of Yale University School of Medicine and Yale Cancer Center, wrote in an invited commentary.

“These data highlight the need for repeat tumor biopsies at the time of resistance to each individual agent to determine if ALK mutations are present in the tumor, and if so, which ones,” Politi and Gettinger wrote. “This practice will allow subsequent treatment to be tailored to the most current mutational state of the tumor.”

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Disclosure: The researchers report consultant/advisory roles with, as well as research grants and honoraria from Chugai, Genentech, Ignyta, Novartis, Pfizer and Ventana. Politi reports a consultant/advisory role with Takeda and a patent relating to EGFR T790M licensed to MolecularMD. Gettinger reports a consultant/advisory role with Ariad Pharmaceuticals.

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PERSPECTIVE
Edward S. Kim

Edward S. Kim

The treatment of patients with non–small cell lung cancer (NSCLC) has evolved tremendously within the past decade. In the beginning, it was based on broad-histology classifications (non–small cell vs. small cell), then based on toxicity and efficacy (bevacizumab [Avastin, Genentech] and pemetrexed [Alimta, Lilly] in squamous histology), and now finally based on molecular characteristics, most notably EGFR mutations and ALK translocations. The treatment paradigms followed as doublet chemotherapy went from the mainstay of treatment to now the default treatment if no mutations are found. Treatments with oral biologic therapy based on specific gene mutations (approximately 20% of patients) have allowed more choices for clinicians. These therapies have especially improved response rates and PFS. As prior efforts to overcoming chemotherapy resistance have failed (second-line treatments have response rates of 2% to 10%), biologic therapies have been developed to treat patients who develop resistance. In patients whose tumors have EGFR-sensitive mutations, treatment with an EGFR tyrosine kinase inhibitor eventually leads to progressive disease. A resistance mutation, T790M, has been identified to occur in 50% to 60% of these patients, and now multiple therapies are in mature development to target this mutation. For patients whose tumors harbor an ALK translocation, crizotinib has been approved for therapy. However, more compounds targeting ALK post-crizotinib are in development. The identification of specific mutations, such as those reported by Katayama and colleagues, is critical in order to personalize therapy. Continued efforts to re-biopsy tumors or to study other means of detecting tumors (eg, liquid biopsies) are urged. Clinical treatment of patients with lung cancer now requires molecular testing upfront as standard of care. Soon, treatment also will require direct re-evaluation of growing tumors in order to maximize treatment options. The rationale of “inconveniencing” the patient with an additional tissue biopsy no longer will be a viable reason for the clinician to default to “standard” chemotherapy.

Edward S. Kim, MD
HemOnc Today Editorial Board member Levine Cancer Institute, Carolinas HealthCare System

Disclosure: Kim reports no relevant financial disclosures.